Caveolin-1 plays a crucial role in atherosclerosis, which is mainly attributed to its effects on low-density-lipoprotein (LDL) transcytosis. However, caveolin-1 has also been implicated in the regulation of inflammation. We investigated the effects of caveolin-1 deficiency in atherosclerosis with its accompanying changes in plaque- and lymphoid-related immunology and inflammation. Cav1−/−Apoe−/− mice exhibited a 15-fold reduction in plaque size with plaques containing fewer macrophages, T cells, and neutrophils. Intravital microscopy revealed 83% less leukocyte adhesion to the vessel wall in Cav1−/−Apoe−/− mice, which could be attributed to reduced endothelial chemokine ligand-2 (CCL-2/MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. Caveolin-1 deficiency resulted in a 57% increase in regulatory T cells and a 4% decrease in CD4+ effector T cells in lymphoid organs. Bone marrow transplantations revealed that Cav1−/−Apoe−/− mice receiving Cav1+/+Apoe−/− or Cav1−/−Apoe−/− bone marrow presented 4- to 4.5-fold smaller plaques with no additional phenotypic changes. In contrast, atherosclerosis was not affected in Cav1+/+ Apoe−/− recipients receiving Cav1−/−Apoe−/− or Cav1+/+ Apoe−/− bone marrow. However, the presence of Cav1−/− Apoe−/− bone marrow was associated with an anti-inflammatory T-cell profile. Our study reveals that nonhematopoietic caveolin-1 determines plaque size, whereas hematopoietic caveolin-1 regulates lymphoid immune-modulation. However, both are required for phenotypic modulation of plaques.—Engel, D., Beckers, L., Wijnands, E., Seijkens, T., Lievens, D., Drechsler, M., Gerdes, N., Soehnlein, O., Daemen, M. J. A. P., Stan, R. V., Biessen, E. A. L., Lutgens, E. Caveolin-1 deficiency decreases atherosclerosis by hampering leukocyte influx into the arterial wall and generating a regulatory T-cell response.